This 2-year R21 application examines the feasibility, efficacy and safety of a novel noninvasive intervention for severe obsessive-compulsive disorder (OCD), informed by neurocircuitry and individualized through functional neuroimaging. Treatment-resistant OCD represents an unmet clinical need. Focal brain stimulation, guided by present understanding of the neurocircuitry underlying OCD, has led to major therapeutic advances as evidenced by the FDA humanitarian approval of deep brain stimulation (DBS). This exciting development has spurred interest in noninvasive alternatives. Repetitive Transcranial Magnetic Stimulation (rTMS) is an attractive option given its noninvasiveness and recent FDA approval for depression. Initial rTMS studies targeting lateral prefrontal regions have had limited success in treating individuals with severe OCD. This is perhaps not surprising since classical DBS targets for OCD are too deep to be accessed by conventional coils. However, our pilot data suggest that low frequency (1 Hz) stimulation of rTMS-accessible targets (e.g. pre-supplementary motor area (SMA)) may be able to improve symptoms of OCD. Recent imaging and physiology studies have suggested a role of hyperactivity in motor circuits (specifically pre-SMA) in OCD, and low frequency rTMS has been reported to have inhibitory effects on motor circuitry. Our pilot work suggests that 1 Hz rTMS delivered to the pre-SMA inhibits motor cortex excitability measures, and that these changes correlate with outcome, consistent with a normalization of baseline hyperexcitability. Here we seek to replicate and extend those findings, using a rigorous randomized sham-controlled trial design. We will implement fMRI-guided rTMS in this protocol to target pre-SMA, in line with recent work suggesting the efficacy of rTMS may be improved through neuronavigation to individual anatomy. Thirty- two patients with severe medication resistant OCD will be randomly assigned to receive active or sham rTMS applied to the pre-SMA daily (5 times/week) for up to four weeks. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) will be used as primary outcome measure. Responders will be followed for 6 months to determine persistence of benefit. We will also collect data on neurophysiological biomarkers shown to be abnormal in OCD and subject to change by rTMS. We propose 3 aims: 1) to determine the feasibility and therapeutic efficacy of fMRI-guided rTMS to pre-SMA in medication-resistant OCD, 2) to evaluate the safety of fMRI-guided rTMS in OCD, and 3) to explore the impact of rTMS to the pre-SMA on TMS measures of motor cortex excitability in OCD. Results will extend our knowledge of the neurocircuitry underlying OCD, clarifying the role of pre-SMA, and evaluating a potential biomarker of mechanistic action. They will also be informative about whether noninvasive neuromodulation with rTMS may be a useful avenue to pursue in the treatment of persons with severe, medication-resistant OCD. If our preliminary findings are supported, this may represent a novel therapeutic avenue for these severely impaired patients. PUBLIC HEALTH RELEVANCE: Severe Obsessive-Compulsive Disorder (OCD) is a disabling illness that causes significant suffering for individuals and their families. This project applies the latest advances in noninvasive modulation of brain function to translate new discoveries in the neurocircuitry of OCD into targeted treatments. The results of this study will contribute to a better understanding of the neural circuits underlying OCD, and will tell us whether imaging-guided repetitive Transcranial Magnetic Stimulation (rTMS) can be of clinical benefit in those patients that do not respond to the conventional treatments.